In response to an oral glucose load, the liver takes up and stores one-third of ingested glucose, a process that is altered by type 2 diabetes mellitus. Earlier studies from our lab have provided information concerning factors that regulate hepatic glucose uptake, including glucose load to the liver, insulin level, and portal glucose delivery. Elevation of muscle glycogen reduces glucose uptake and glycogen synthesis, however the effect of hepatic glycogen level on hepatic glucose uptake and disposition is not known. To investigate this topic, we will use the 18 hour fasted conscious dog. During the first four hours of each study, all animals will receive peripheral infusion of SRIF to disable the endocrine pancreas, and basal intraportal replacement of insulin and glucagon. Coincidently, glucose load to the liver will be doubled, and an intraportal infusion of saline or fructose will be started. Fructose will be given at rates calculated to increase hepatic glycogen by 40 and 80 mg/g, respectively. The fructose infusion will be followed by a two hour control period, during which basal replacement of hormones and substrates (except fructose) will continue, allowing hepatic glucose metabolism to return to baseline. The final two hours (i.e., the experimental period) will be characterized by either the intraportal infusion of insulin at four times basal, or insulin infusion plus intraportal infusion of glucose at a rate of 4 mg/kg/min. In this way we will be able to examine the effect of hepatic glycogen loading on the ability of insulin to alter net hepatic glucose uptake and hepatic glucose disposition. We will also be able to determine the impact of hepatic glycogen loading on the impact of the portal glucose signal on hepatic uptake of glucose and its fate in the liver. PUBLIC HEALTH RELEVANCE: In response to feeding, the liver takes up a significant amount of the glucose load, a process that is impaired in people with type 2 diabetes mellitus, contributing to the high blood glucose levels seen in this population. Medications for the treatment of diabetes mellitus are being developed to increase uptake and storage of glucose by the liver, but the effect of increasing liver glycogen levels is not known, and may limit the utility of such approaches. More needs to be known about the impact of hepatic glycogen on glucose metabolism by the liver, as such knowledge could lead to an improved understanding of disease states that are characterized by impaired hepatic glucose uptake, such as type 2 diabetes mellitus.